The present invention relates to methods for producing chiral aldehydes by the enantioselective hydroformylation of prochiral substrates with the aid of a catalyst consisting of a transition metal and a chiral phosphorus-containing ligand which contains aromatic rings substituted with perfluoroalkyl groups.
The addition of hydrogen and carbon monoxide to prochiral Cxe2x95x90C double bonds using chiral catalysts (enantioselective hydroformylation) is an efficient method for the synthesis of chiral, non-racemic aldehydes (Catalytic Asymmetric Synthesis, Ed.: I. Ojima, VCH, Weinheim, 1993, p. 273). This reaction type has found great interest, in particular, as a possible access to chiral building blocks for the production of flavoring agents, cosmetics, plant protection agents, food additives (e.g., vitamins), and pharmaceutical agents (Chirality 1991, 3, 355). There may be mentioned, in particular, the preparation of the anti-inflammatory and analgetic drugs ibuprofen and naproxen by the oxidation of the corresponding aldehydes, which can be obtained by enantioselective hydroformylation. Further, chiral aldehydes offer access to xcex1-amino acids, antibiotics based on polyethers and macrocyclic antitumor drugs.
For an efficient enantioselective hydroformylation, the following criteria must be met: 1. high activity of the catalyst; 2. high chemo- and regioselectivity for the formation of the desired aldehyde; 3. high enantioselectivity in favor of the desired enantiomer. The methods known today for enantioselective hydroformylation use catalyst systems which contain a transition metal center in the presence of a chiral coordinated compound (ligand). As the transition metal, rhodium and platinum are mainly used, but other metals including cobalt, iridium or ruthenium also exhibit catalytic activity. As the ligands, chiral phosphorus compounds, above all, have proven useful, the efficiency of the systems being strongly influenced by the structure of the ligands (Chem. Rev. 1995, 95, 2485).
The as yet most efficient catalyst system for enantioselective hydroformylation is based on a rhodium catalyst which contains the ligand (R)-2-(diphenylphosphino)-1,1xe2x80x2-binaphthol-2xe2x80x2-yl (S)-1,1xe2x80x2-binaphthol-2,2xe2x80x2-diyl phosphite, (R,S)-binaphos (Topics in Catalysis 1997, 4, 175; EP 0 614 870 A3) and related ligands (EP 0 684 249 A1, EP 0 647 647 A1). The main drawbacks of the methods relying on this catalyst system include, on the one hand, the limited regioselectivity for the formation of the desired branched isomer in the hydroformylation of vinyl aromatics (see Scheme 1). The regioselectivity with (R,S)-binaphos is, for example, about 88%, and the 12% of linear aldehyde is a worthless by-product which has to be separated off tediously and disposed of. On the other hand, these catalyst systems work with the greatest efficiency only when solvents are used which are toxicologically and ecologically harmful, such as benzene. 
Compressed carbon dioxide in the liquid (liqCO2) or supercritical state (ScCO2) is an interesting solvent for performing catalytic reactions because it is toxicologically and ecologically safe, in contrast to conventional organic solvents. A survey of catalytic reactions in scCO2 is found in Science 1995, 269, 1065. To date, liqCO2 has been employed as a reaction medium only in a few cases, e.g., Angew. Chem. 1997, 109, 2562. However, the ligand (R,S)-binaphos cannot be employed efficiently in compressed carbon dioxide since the enantioselectivity is drastically decreased in the presence of compressed carbon dioxide (S. Kainz, W. Leitner, Catal. Lett., in press).
The use of perfluorinated alkyl chains for increasing the solubility of arylphosphorus ligands in supercritical carbon dioxide and the use of corresponding achiral ligands in the rhodium-catalyzed hydroformylation in scCO2 has been described in the German Offenlegungsschrift DE 197 02 025 A1. However, an increased regioselectivity in favor of the linear achiral aldehyde is found with the ligands described therein. The use of scCO2 is a precondition for achieving high reaction rates, while liqCO2 results in inefficiently slow reactions (D. Koch, W. Leitner, J. Am. Chem. Soc, in press).
We now describe a novel method for producing chiral aldehydes by the enantioselective hydroformylation of prochiral substrates with the aid of a catalyst consisting of a transition metal and a chiral ligand, characterized in that said chiral ligand is a compound of general formula 1 
wherein the rings R7-R10 drawn with dotted lines are optional and one or more of rings R1-R6 or R7-R10 are substituted with one or more independently selected substituents of general formula xe2x80x94(CH2)x(CF2)yF(x=0-5; y=1-12) or their branched isomers. The synthetic route for such a ligand is shown in Scheme 2, illustrated for the ligand (R,S)1a. 
Surprisingly, in the hydroformylation of prochiral substrates, the use of these ligands results in a higher regioselectivity in favor of the branched, chiral aldehyde isomers as compared to a reaction performed with corresponding unsubstituted compounds, but without adversely affecting the enantioselectivity. At the same time, these substituents allow to perform the mentioned processes in compressed carbon dioxide as a reaction medium, whereby the use of toxic or ecologically harmful solvents is avoided. Unexpectedly, the hydroformylation can be performed not only in supercritical CO2 (scCO2), but also in liquid CO2 (liqCO2), which enables working at lower temperatures and pressures during the reaction. Making use of the extractive properties of CO2, the products and catalysts can be separated effectively and carefully, and the catalysts are recovered in an active form.
The catalysts for the enantioselective hydroformylation can be either employed in the form of isolated complex compounds which already contain the chiral ligands of formula 1, or they are formed in situ from a ligand of formula 1 and a suitable metal-containing precursor. A detailed description of possible catalyst systems is found, for example, in Chem. Rev. 1995, 95, 2485. In the present method, compounds or salts of transition metals can be employed as metal components. Preferred are catalysts based on the metals Fe, Co, Ir, Ru, Pt, Rh, especially preferred Pt and Rh. Particularly preferred metal components include, for example, RhCl3nH2O, [Rh2(OAc)4](OAc=O(O)CCH3)], [(L)2Rh(xcexc-Cl)2Rh(L)2](L=olefin, CO, PR3 etc.), [(L)2Rh(acac)](acac=acetylacetonate) or [(L)2PtCl2]/SnCl2, without intending that this enumeration should imply a limitation. The optimum molar ratio of ligand/metal depends on the respective system, but should usually be between 1:1 and 10:1, preferably between 1:1 and 4:1.
Possible substrates for the enantioselective hydroformylation using the ligands of general formula 1 include all compounds which contain a prochiral Cxe2x95x90C double bond having an appropriate reactivity. Examples of such compounds can be seen from the following group, without intending that the selection of the compounds should imply a limitation to the scope of application: vinylaromatics (e.g., styrene and substituted styrene derivatives, such as chlorobenzene, para-isobutylstyrene or vinylnaphthyl and its derivatives), vinylpyridine, acrylic acid and its derivatives (e.g., xcex1-acetamidoacrylic acid ester), vinyl acetate, vinyl phthalates, allyl acetate, indene, dihydro-2-pyridones, norbornene, and many more. A complete solubility of the substrates and products during the entire duration of the reaction is no necessary precondition for the reaction to proceed effectively when it is performed in compressed CO2. The molar ratio of substrate and catalyst is mainly determined by economical considerations and represents a compromise between the costs for the catalyst and the practically acceptable reaction rate. Therefore, the optimum value may vary within a broad range depending on the substrate and catalyst. With the catalyst, 1a /Rh, ratios of substrate/catalyst of between 100:1 and 100,000:1 are possible, a ratio of between 500:1 and 10,000:1 being preferably used.
The gases H2 and CO can be supplied to the reactor either separately or as a mixture. The partial pressure p of the individual gases is within a range of between 1 and 100 bar, preferably within a range of between 5 and 50 bar. When the reaction is performed in carbon dioxide, the reaction gases can be introduced prior to, after or together with the CO2. The amount of CO2 is selected such that the total pressure at the reaction temperature, p0total, is within a range of between 20 and 500 bar, preferably within a range of between 50 and 350 bar. The reaction temperature may be varied within a broad range and is situated between xe2x88x9220xc2x0 C. and 100xc2x0 C., preferably between 20xc2x0 C. and 60xc2x0 C. At reaction temperatures below the critical temperature of CO2 (Tc=31xc2x0 C.), there is always a liquid CO2 phase, wherein the total pressure, ptotal, at T less than 31xc2x0 C. should preferably be between 50 and 150 bar. At temperatures above the critical temperature (T greater than 31xc2x0 C.), the phase behavior depends on the substrates employed and the composition of the reaction mixture, and the total pressure, p0total, should be within the preferred range of between 75 and 350 bar. If conducted without carbon dioxide, the reaction is performed either in the absence of an additional solvent or with the use of any organic solvent which does not adversely affect the reaction. Preferred solvents include, for example, pentane, hexane, toluene, benzene, diethyl ether, tetrahydrofuran, chloroform, methylene chloride, perfluorinated hydrocarbons or perfluorinated polyethers.
When the reaction is performed in compressed carbon dioxide, after completion, the product can be separated from the catalyst as described in DE 197 02 025 A1 by extraction with CO2, the catalyst remaining in the reactor in an active and selective form. The combination of reaction and extraction can be realized in a batch, semi-batch or continuous process.